Breast cancer is by far the most common cancer among women. Each year, more than 180,000 and 1 million women in the U.S. and worldwide, respectively, are diagnosed with breast cancer. Breast cancer is the leading cause of death for women between ages 50-55, and is the most common non-preventable malignancy in women in the Western Hemisphere. An estimated 2,167,000 women in the United States are currently living with the disease (National Cancer Institute, Surveillance Epidemiology and End Results (NCI SEER) program, Cancer Statistics Review (CSR), www-seer.ims.nci.nih.gov/Publications/CSR1973 (1998)). Based on cancer rates from 1995 through 1997, a report from the National Cancer Institute (NCI) estimates that about 1 in 8 women in the United States (approximately 12.8 percent) will develop breast cancer during her lifetime (NCI's Surveillance, Epidemiology, and End Results Program (SEER) publication SEER Cancer Statistics Review 1973-1997). Breast cancer is the second most common form of cancer, after skin cancer, among women in the United States. An estimated 250,100 new cases of breast cancer are expected to be diagnosed in the United States in 2001. Of these, 192,200 new cases of more advanced (invasive) breast cancer are expected to occur among women (an increase of 5% over last year), 46,400 new cases of early stage (in situ) breast cancer are expected to occur among women (up 9% from last year), and about 1,500 new cases of breast cancer are expected to be diagnosed in men (Cancer Facts & Figures 2001 American Cancer Society). An estimated 40,600 deaths (40,300 women, 400 men) from breast cancer are expected in 2001. Breast cancer ranks second only to lung cancer among causes of cancer deaths in women. Nearly 86% of women who are diagnosed with breast cancer are likely to still be alive five years later, though 24% of them will die of breast cancer after 10 years, and nearly half (47%) will die of breast cancer after 20 years.
Every woman is at risk for breast cancer. Over 70 percent of breast cancers occur in women who have no identifiable risk factors other than age (U.S. General Accounting Office. Breast Cancer, 1971-1991: Prevention, Treatment and Research. GAO/PEMD-92-12; 1991). Only 5 to 10% of breast cancers are linked to a family history of breast cancer (Henderson I C, Breast Cancer. In: Murphy G P, Lawrence W L, Lenhard R E (eds). Clinical Oncology. Atlanta, Ga.: American Cancer Society; 1995:198-219).
Each breast has 15 to 20 sections called lobes. Within each lobe are many smaller lobules. Lobules end in dozens of tiny bulbs that can produce milk. The lobes, lobules, and bulbs are all linked by thin tubes called ducts. These ducts lead to the nipple in the center of a dark area of skin called the areola. Fat surrounds the lobules and ducts. There are no muscles in the breast, but muscles lie under each breast and cover the ribs. Each breast also contains blood vessels and lymph vessels. The lymph vessels carry colorless fluid called lymph, and lead to the lymph nodes. Clusters of lymph nodes are found near the breast in the axilla (under the arm), above the collarbone, and in the chest.
Breast tumors can be either benign or malignant. Benign tumors are not cancerous, they do not spread to other parts of the body, and are not a threat to life. They can usually be removed, and in most cases, do not come back. Malignant tumors are cancerous, and can invade and damage nearby tissues and organs. Malignant tumor cells may metastasize, entering the bloodstream or lymphatic system. When breast cancer cells metastasize outside the breast, they are often found in the lymph nodes under the arm (axillary lymph nodes). If the cancer has reached these nodes, it means that cancer cells may have spread to other lymph nodes or other organs, such as bones, liver, or lungs.
Major and intensive research has been focused on early detection, treatment and prevention. This has included an emphasis on determining the presence of precancerous or cancerous ductal epithelial cells. These cells are analyzed, for example, for cell morphology, for protein markers, for nucleic acid markers, for chromosomal abnormalities, for biochemical markers, and for other characteristic changes that would signal the presence of cancerous or precancerous cells. This has led to various molecular alterations that have been reported in breast cancer, few of which have been well characterized in human clinical breast specimens. Molecular alterations include presence/absence of estrogen and progesterone steroid receptors, HER-2 expression/amplification (Mark H F, et al. HER-2/neu gene amplification in stages I-IV breast cancer detected by fluorescent in situ hybridization. Genet Med; 1(3):98-103 1999), Ki-67 (an antigen that is present in all stages of the cell cycle except G0 and used as a marker for tumor cell proliferation, and prognostic markers (including oncogenes, tumor suppressor genes, and angiogenesis markers) like p53, p27, Cathepsin D, pS2, multi-drug resistance (MDR) gene, and CD31.
Tamoxifen is the antiestrogen agent most frequently prescribed in women with both early stage and metastatic hormone receptor-positive breast cancer (for reviews, see Clarke, R. et al. “Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.” Oncogene 22, 7316-39 (2003) and Jordan, C. “Historical perspective on hormonal therapy of advanced breast Cancer.” Clin. Ther. 24 Suppl A, A3-16 (2002)). In the adjuvant setting, tamoxifen therapy results in a 40-50% reduction in the annual risk of recurrence, leading to a 5.6% improvement in 10 year survival in lymph node negative patients, and a corresponding 10.9% improvement in node-positive patients (Group, E.B.C.T.C. Tamoxifen for early breast cancer. Cochrane Database Syst Rev, CD000486 (2001)). Tamoxifen is thought to act primarily as a competitive inhibitor of estrogen binding to estrogen receptor (ER). The absolute levels of ER expression, as well as that of the progesterone receptor (PR, an indicator of a functional ER pathway), are currently the best predictors of tamoxifen response in the clinical setting (Group, (2001) and Bardou, V. J. et al. “Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases.” J Clin Oncol 21, 1973-9 (2003)).
However, 25% of ER+/PR+ tumors, 66% of ER+/PR− cases and 55% of ER−/PR+ cases fail to respond, or develop early resistance to tamoxifen, through mechanisms that remain largely unclear (see Clarke et al.; Nicholson, R. I. et al. “The biology of antihormone failure in breast cancer.” Breast Cancer Res Treat 80 Suppl 1, S29-34; discussion S35 (2003) and Osborne, C. K. et al. “Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer.” Breast 12, 362-7 (2003)). Currently, no reliable means exist to allow the identification of these non-responders. In these patients, the use of alternative hormonal therapies, such as the aromatase inhibitors letrozole and anastrozole (Ellis, M. J. et al. “Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptorpositive primary breast cancer: evidence from a phase III randomized trial.” J Clin Oncol 19, 3808-16 (2001); Buzdar, A. U. “Anastrozole: a new addition to the armamentarium against advanced breast cancer.” Am J Clin Oncol 21, 161-6 (1998); and Goss, P. E. et al. “A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.” N Engl J Med 349, 1793-802 (2003)); chemotherapeutic agents, or inhibitors of other signaling pathways, such as trastuzmab and gefitinib might offer the possibility of improving clinical outcome. Therefore, the ability to accurately predict tamoxifen treatment outcome should significantly advance the management of early stage breast cancer by identifying patients who are unlikely to benefit from TAM so that additional or alternative therapies may be sought.
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